Degree

Department

Document Type

Dissertation

Abstract

Fetal stress has been linked to adult atherosclerosis, obesity, and diabetes. Epidemiology studies have associated fetal exposure to maternal smoking and post-natal exposure to environmental tobacco smoke (ETS) with increased asthma risk. We tested the hypothesis, in a mouse model of asthma, that ETS exposure in utero alters airway function and respiratory immune responses in adult offspring. Pregnant BALB/c mice were exposed daily to ETS or filtered air (AIR). Neonatal gene expression was assessed. Offspring inhaled aerosolized ovalbumin (OVA) or saline in weeks 7-8. Regardless of whether they inhaled OVA or saline, mice were sensitized by OVA injections in weeks 11 and 13 followed by OVA aerosol challenge in weeks 14-15. At weeks 6, 10, and 15, we assessed OVA-specific serum immunoglobins, bronchoalveolar lavage cells and cytokines, lung and nasal histopathology, lung gene expression, and airway hyperresponsiveness (AHR). Neonatal mice demonstrated slight but potentially critical differences in gene expression related to their exposure to ETS in utero. At 6 weeks, there were no significant differences between mice exposed to ETS in utero and those exposed to AIR in utero. At 10 weeks, following OVA aerosol, mice exposed to ETS in utero displayed greater AHR than mice exposed to AIR in utero (ƒÑ = 0.05), unaccompanied by changes in histopathology, cytokine profile, or antibody levels. However, there were significant differences in gene expression between these 10 week groups. At 15 weeks, mice that had inhaled saline in weeks 7-8 developed airway inflammation: eosinophilia (ƒÑ = 0.05), IL-5 (ƒÑ = 0.05) and AHR (ƒÑ = 0.05) were greater in mice exposed to ETS in utero vs. mice exposed to AIR in utero. Mice that had inhaled OVA in weeks 7-8 demonstrated no airway inflammation after sensitization and challenge and those exposed to ETS in utero had suppressed immune and inflammatory responses. Consistent with other findings at 15 weeks, there were significant differences in gene expression between mice receiving ETS exposure in utero and those receiving AIR exposure in utero. ETS exposure in utero exacerbates subsequent adult responses to initial allergen exposure and causes altered gene expression, especially with additional lung perturbation.